EP0965574B1 - Process for enantioselective hydrogenation - Google Patents

Process for enantioselective hydrogenation Download PDF

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Publication number
EP0965574B1
EP0965574B1 EP99111460A EP99111460A EP0965574B1 EP 0965574 B1 EP0965574 B1 EP 0965574B1 EP 99111460 A EP99111460 A EP 99111460A EP 99111460 A EP99111460 A EP 99111460A EP 0965574 B1 EP0965574 B1 EP 0965574B1
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Prior art keywords
alkyl
cycloalkyl
aryl
acyl
heteroaryl
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EP0965574A2 (en
EP0965574A3 (en
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Paul Prof. Knochel
Juan José Dr. Almena Perea
Karlheinz Prof. Drauz
Ingo Dr. Klement
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umicor AG & Co KG
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Degussa GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/36—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by hydrogenation of carbon-to-carbon unsaturated bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/303—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by hydrogenation of unsaturated carbon-to-carbon bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the enantioselective introduction of stereogenic centers in organic molecules by homogeneously catalyzed hydrogenation is for special applications on an industrial scale established.
  • the enantioselective products are valuable Starting substances for the production of bioactive agents.
  • Yamamoto et al. (Bull. Chem. Soc., Jpn., 1980, 53, 1132-1137) reported the use of non- C 2 -symmetric ferrocenyl (bis-tertiary phosphine) ligands in enantioselective homogeneous catalytic hydrogenation. With these ligands, however, only very isolated enantiomeric excesses are obtained.
  • the object of the present invention is to specify a process for the homogeneous catalytic enantioselective hydrogenation of further unsaturated systems with the aid of C 2 -symmetric ferrocenyl catalysts.
  • the inventive method can advantageously in a temperature between 0 ° C and 150 ° C, preferably between 20 ° C and 80 ° C, are performed.
  • the hydrogen pressure should be between during the reaction 10 kPa and 10000 kPa, preferably between 50 kPa and 8000 kPa, lie.
  • solvents are used, provided they interfere these are not in terms of yield and chiral induction.
  • ethers such as THF, DME, MTBE, alcohols, such as MeOH, EtOH, propanol, butanol.
  • the ferrocenyl catalysts show excellent values in the homogeneous enantioselective catalytic hydrogenation, as shown in Table 1 below.
  • the catalyst concentration is 1% in the mentioned Examples already very low. She can, however, for technical application. Both is for the application of the ligands of the invention in technical scale very beneficial, since the cost of the according to this method obtained products accordingly lower and thus a higher economic Benefits of using state-of-the-art ligand systems the technology is guaranteed.
  • the radical R 5 in the complexes may, inter alia, for attachment of the complexes of the invention to a polymeric matrix such.
  • a polymeric matrix such as a linear PMMA, polystyrene or PEG and a non-linear dendrimer can be used.
  • the attachment of the radical R 5 to the cyclopentadienyl ring of the complex according to the invention is variable with respect to the free positions and with respect to the ring. Thus, the attachment of the polymer to a ring is sufficient.
  • radicals it is possible to use all radicals which are suitable for this purpose.
  • a suitable overview of the molecular enlargement of complex catalysts offers (Tetrahedron Asymmetry 1998, 9 , 691-696).
  • the radical R 5 consists of the arrangement BXZ, where B is a radical of the group CR 8 2 , NR 8 , O, S, SiR 8 2 , X is a spacer, such as. B. 1,4 '-biphenyl, 1-, 2-ethylene, 1-, 3-propylene, PEG- (2-10), and Z is a functional group such.
  • B a radical of the group CR 8 2 , NR 8 , O, S, SiR 8 2
  • X is a spacer, such as.
  • Z is a functional group such.
  • the radicals R 5 of the two cyclopentadienyl rings can be linked to one another via an ⁇ , ⁇ , - (C 2 -C 4 ) -alkylene bridge.
  • C 1 -C 18 alkyl are methyl, ethyl, n- propyl, isopropyl, n- butyl, isobutyl, sec- butyl, tert- butyl, pentyl, hexyl, heptyl or octyl up to a 18 C atoms having all the rest of its binding isomers.
  • the radical (C 1 -C 18 ) -alkoxy corresponds to the radical (C 1 -C 18 ) -alkyl, with the proviso that it is bonded to the molecule via an oxygen atom.
  • (C 2 -C 18 ) alkoxyalkyl residues in which the alkyl chain is interrupted by at least one oxygen function, whereby not two oxygen atoms can be linked together.
  • the number of carbon atoms indicates the total number of carbon atoms contained in the radical.
  • the radicals just described may be monosubstituted or polysubstituted by halogens and / or N, O, P, S atom-containing radicals.
  • These are in particular alkyl radicals of the abovementioned type which have one or more of these heteroatoms in their chain or which are bonded to the molecule via one of these heteroatoms.
  • the statements made above apply correspondingly to a max. 8 C atoms containing alkyl radical.
  • (C 3 -C 8 ) -cycloalkyl is meant cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radicals, etc. These may be substituted by one or more halogens and / or N, O, P, S atom-containing radicals and / or N-, O-, P-, S-atom-containing radicals in the ring, such as. 1-, 2-, 3-, 4-piperidyl, 1-, 2-, 3-pyrrolidinyl, 2-, 3-tetrahydrofuryl, 2-, 3-, 4-morpholinyl.
  • a (C 3 -C 8 ) -cycloalkyl (C 1 -C 8 ) -alkyl radical denotes a cycloalkyl radical as described above which is bonded to the molecule via an alkyl radical as indicated above.
  • (C 1 -C 18 ) -Acyloxy in the context of the invention means an alkyl radical as defined above with max. 18 C atoms, which is bound to the molecule via a COO function.
  • (C 1 -C 8 ) acyloxy the corresponding applies.
  • (C 1 -C 18 ) acyl in the context of the invention means an alkyl radical as defined above with max. 18 C atoms, which is bound to the molecule via a CO function.
  • (C 1 -C 8 ) acyl the corresponding applies.
  • C 1 -C 8 -alkyloxycarbonyl radical means an alkyl radical as defined above with max. 8 C atoms, which is bound to the molecule via an OCO function.
  • a (C 6 -C 18 ) -aryl radical is meant an aromatic radical having 6 to 18 C atoms.
  • aromatic radicals include, in particular, compounds such as phenyl, naphthyl, anthryl, phenanthryl and biphenyl radicals, which are optionally substituted by (C 1 -C 8 ) -alkoxy, NR 6 R 7 , (C 1 -C 8 ) -acyl, (C 1 -C 8 ) acyloxy may be substituted.
  • a (C 7 -C 19 ) -aralkyl radical is a (C 6 -C 18 ) -aryl radical bonded to the molecule via a (C 1 -C 8 ) -alkyl radical.
  • a (C 3 -C 18 ) -heteroaryl radical denotes a five-, six- or seven-membered aromatic ring system comprising 3 to 18 C atoms, which heteroatoms such.
  • heteroaromatics are radicals such as 1-, 2-, 3-furyl, such as 1-, 2-, 3-pyrrolyl, 1-, 2-, 3-thienyl, 2-, 3-, 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7-indolyl, 3-, 4-, 5-pyrazolyl, 2-, 4-, 5-imidazolyl, acridinyl, quinolinyl, phenanthridinyl, 2-, 4- , 5-, 6-pyrimidinyl.
  • radicals such as 1-, 2-, 3-furyl, such as 1-, 2-, 3-pyrrolyl, 1-, 2-, 3-thienyl, 2-, 3-, 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7-indolyl, 3-, 4-, 5-pyrazolyl, 2-, 4-, 5-imidazolyl, acridinyl, quinolinyl, phenanthridinyl, 2-, 4- , 5-, 6-pyrimidinyl.
  • heteroaralkyl is meant a heteroaromatic system corresponding to the (C 7 -C 19 ) aralkyl radical.
  • Suitable halogens are fluorine, chlorine, bromine and iodine.
  • salts ionic addition compounds of strong acids such as HCl, HBr, H 2 SO 4 , H 3 PO 4 , CF 3 COOH, p-toluenesulfonic acid, methanesulfonic acid and the molecule under consideration.
  • PEG means polyethylene glycol
  • enantiomerically enriched is used in the context the invention, the proportion of an enantiomer in admixture with its optical antipode in a range of> 50% and ⁇ 100% understood.
  • diastereomerically enriched means the excess of a diastereomer over one or several others.
  • a polymeric Matrix such as As linear PMMA, polystyrene or PEG and nonlinear dendrimers, understood.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Description

Die vorliegende Erfindung betrifft ein Verfahren zur homogenen katalytischen enantioselektiven Hydrierung von Verbindungen der allgemeinen Formel (I)

Figure 00010001
worin

  • n 0 oder 1 ist,
  • R = H, (C1-C18)-Alkyl, (C6-C18)-Aryl, (C7-C19)-Aralkyl, (C1-C8)-Alkyl- (C6-C18)-Aryl, (C3-C8)-Cycloalkyl, (C1-C8)-Alkyl- (C3-C8)-Cycloalkyl, (C3-C8)-Cycloalkyl- (C1-C8)-Alkyl,
    oder eine Carboxyschutzgruppe bedeutet,
  • R' = H, (C1-C18)-Alkyl, (C6-C18)-Aryl, (C7-C19)-Aralkyl, (C3-C18)-Heteroaryl, (C4-C19)-Heteroaralkyl, (C1-C8)-Alkyl- (C6-C18)-Aryl, (C1-C8)-Alkyl- (C3-C19)-Heteroaryl, (C3-C8)-Cycloalkyl, (C1-C8)-Alkyl- (C3-C8)-Cycloalkyl, (C3-C8)-Cycloalkyl-(C1-C8)-Alkyl, wobei die eben genannten Reste mit (C1-C8)-Acyl oder (C1-C8)-Alkyloxycarbonyl substituiert sein können, bedeutet, wobei (C3-C18)-Heteroarylrest ein fünf-, sechs- oder siebengliedriges aromatisches Ringsystem aus 3 bis 18 C-Atomen, welches Heteroatome ausgewählt aus Stickstoff, Sauerstoff oder Schwefel im Ring aufweist, bezeichnet,
  • X = O, CHR'', NR'', ist,
  • R'' = H, OH, R', (C1-C18)-Alkoxy, (C2-C18)-Alkoxyalkyl, (C1-C18)-Acyl, (C1-C18)-Acyloxy sein kann, wobei für verschiedene Positionen im Molekül R'' verschiedene Gestalt annehmen kann,
    • oder R und oder R' und R'' oder R'' und R sind über eine (C1-C4)-Brücke miteinander verbunden, welche einfach oder mehrfach mit linear oder verzweigten (C1-C8)-Alkyl, (C1-C8)-Acyl, (C1-C8)-Alkoxy, (C2-C8)-Alkoxyalkylresten substituiert sein und/oder im Ring Heteroatome ausgewählt aus N, O, P, S enthalten kann,
    oder worin
  • n 1 ist,
  • R = H, (C1-C18)-Alkyl, (C6-C18)-Aryl, (C7-C19)-Aralkyl, (C1-C8)-Alkyl-(C6-C18)-Aryl, (C3-C8)-Cycloalkyl, (C1-C8)-Alkyl-(C3-C8)-Cycloalkyl, (C3-C8)-Cycloalkyl-(C1-C8)-Alkyl,
    oder eine Carboxyschutzgruppe bedeutet,
  • R' = H, (C1-C18)-Alkyl, (C6-C18)-Aryl, (C7-C19)-Aralkyl, (C3-C18)-Heteroaryl, (C4-C19)-Heteroaralkyl, (C1-C8)-Alkyl-(C6-C18)-Aryl, (C1-C8)-Alkyl-(C3-C19)-Heteroaryl, (C3-C8)-Cycloalkyl, (C1-C8)-Alkyl- (C3-C8)-Cycloalkyl, (C3-C8)-Cycloalkyl-(C1-C8)-Alkyl, wobei die eben genannten Reste mit (C1-C8)-Acyl oder (C1-C8)-Alkyloxycarbonyl substituiert sein können, bedeutet,
    wobei (C3-C18)-Heteroarylrest ein fünf-, sechs- oder siebengliedriges aromatisches Ringsystem aus 3 bis 18 C-Atomen, welches Heteroatome ausgewählt aus Stickstoff, Sauerstoff oder Schwefel im Ring aufweist, bezeichnet,
  • X = NR'' ist,
  • R'' = H, OH, R', (C1-C18)-Alkoxy, (C2-C18)-Alkoxyalkyl, (C1-C18)-Acyl, (C1-C18)-Acyloxy sein kann, wobei für verschiedene Positionen R'' verschiedene Gestalt annehmen kann,
    •  oder R und R' oder R' und R'' oder R'' und R sind über eine (C1-C4)-Brücke miteinander verbunden, welche einfach oder mehrfach mit linear oder verzweigten (C1-C8)-Alkyl, (C1-C8)-Acyl, (C1-C8)-Alkoxy, (C2-C8)-Alkoxyalkylresten substituiert sein und/oder im Ring Heteroatome ausgewählt aus N, O, P, S enthalten kann, mit Hilfe von C 2-symmetrischen Ferrocenylkatalysatoren.The present invention relates to a process for the homogeneous catalytic enantioselective hydrogenation of compounds of the general formula (I)
    Figure 00010001
    wherein
  • n is 0 or 1,
  • R = H, (C 1 -C 18 ) -alkyl, (C 6 -C 18 ) -aryl, (C 7 -C 19 ) -aralkyl, (C 1 -C 8 ) -alkyl- (C 6 -C 18 ) Aryl, (C 3 -C 8 ) cycloalkyl, (C 1 -C 8 ) alkyl (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 ) cycloalkyl (C 1 -C 8 ) alkyl,
    or a carboxy-protecting group,
  • R '= H, (C 1 -C 18 ) -alkyl, (C 6 -C 18 ) -aryl, (C 7 -C 19 ) -aralkyl, (C 3 -C 18 ) -heteroaryl, (C 4 -C 19 ) heteroaralkyl, (C 1 -C 8 ) alkyl (C 6 -C 18 ) aryl, (C 1 -C 8 ) alkyl (C 3 -C 19 ) heteroaryl, (C 3 -C 8 ) -cycloalkyl, (C 1 -C 8 ) -alkyl (C 3 -C 8 ) -cycloalkyl, (C 3 -C 8 ) -cycloalkyl- (C 1 -C 8 ) -alkyl, where the abovementioned radicals with (C 1 -C 8 ) -acyl or (C 1 -C 8 ) -alkyloxycarbonyl, where (C 3 -C 18 ) -heteroaryl radical is a five-, six- or seven-membered aromatic ring system from 3 to 18 C atoms which has heteroatoms selected from nitrogen, oxygen or sulfur in the ring denotes
  • X = O, CHR ", NR",
  • R "= H, OH, R ', (C 1 -C 18 ) -alkoxy, (C 2 -C 18 ) -alkoxyalkyl, (C 1 -C 18 ) -acyl, (C 1 -C 18 ) -acyloxy which may take different forms for different positions in the molecule R '',
    • or R and / or R 'and R "or R" and R are connected to one another via a (C 1 -C 4 ) bridge which is mono- or polysubstituted by linear or branched (C 1 -C 8 ) -alkyl, ( C 1 -C 8 ) -acyl, (C 1 -C 8 ) -alkoxy, (C 2 -C 8 ) -alkoxyalkyl radicals and / or may contain in the ring heteroatoms selected from N, O, P, S,
    or in which
  • n is 1,
  • R = H, (C 1 -C 18 ) -alkyl, (C 6 -C 18 ) -aryl, (C 7 -C 19 ) -aralkyl, (C 1 -C 8 ) -alkyl- (C 6 -C 18 ) Aryl, (C 3 -C 8 ) cycloalkyl, (C 1 -C 8 ) alkyl (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 ) cycloalkyl (C 1 -C 8 ) alkyl,
    or a carboxy-protecting group,
  • R '= H, (C 1 -C 18 ) -alkyl, (C 6 -C 18 ) -aryl, (C 7 -C 19 ) -aralkyl, (C 3 -C 18 ) -heteroaryl, (C 4 -C 19 ) heteroaralkyl, (C 1 -C 8 ) alkyl (C 6 -C 18 ) aryl, (C 1 -C 8 ) alkyl (C 3 -C 19 ) heteroaryl, (C 3 -C 8 ) -cycloalkyl, (C 1 -C 8 ) -alkyl (C 3 -C 8 ) -cycloalkyl, (C 3 -C 8 ) -cycloalkyl- (C 1 -C 8 ) -alkyl, where the abovementioned radicals with (C 1 -C 8 ) -acyl or (C 1 -C 8 ) -alkyloxycarbonyl,
    (C 3 -C 18 ) heteroaryl radical denotes a five-, six- or seven-membered aromatic ring system of 3 to 18 C atoms which has heteroatoms selected from nitrogen, oxygen or sulfur in the ring,
  • X is NR ",
  • R "= H, OH, R ', (C 1 -C 18 ) -alkoxy, (C 2 -C 18 ) -alkoxyalkyl, (C 1 -C 18 ) -acyl, (C 1 -C 18 ) -acyloxy which may take different forms for different positions R '',
    • or R and R 'or R' and R "or R" and R are linked together via a (C 1 -C 4 ) bridge which is mono- or polysubstituted by linear or branched (C 1 -C 8 ) -alkyl , (C 1 -C 8 ) -acyl, (C 1 -C 8 ) -alkoxy, (C 2 -C 8 ) -alkoxyalkyl radicals, and / or may contain in the ring heteroatoms selected from N, O, P, S, with the help of C 2 -symmetric ferrocenyl catalysts.

    Die durch die erfindungsgemäße enantioselektive Hydrierung hergestellten Derivate können als chirale Intermediate in der organischen Synthese verwendet werden.The enantioselective hydrogenation according to the invention Derivatives prepared as chiral intermediates in the organic synthesis can be used.

    Die enantioselektive Einführung von stereogenen Zentren in organische Moleküle durch homogen katalysierte Hydrierung ist für spezielle Anwendungen im industriellen Maßstab etabliert. Die enantioselektiven Produkte sind wertvolle Ausgangssubstanzen zur Herstellung bioaktiver Wirkstoffe.The enantioselective introduction of stereogenic centers in organic molecules by homogeneously catalyzed hydrogenation is for special applications on an industrial scale established. The enantioselective products are valuable Starting substances for the production of bioactive agents.

    Der Einsatz von Bisphosphinkatalysatoren für die enantioselektive homogene katalytische Hydrierung für den eben genannten Zweck ist wohl bekannt (Burk et al., Tetrahedron 1994, 4399)The use of bisphosphine catalysts for the enantioselective homogeneous catalytic hydrogenation for the the purpose just mentioned is well known (Burk et al., Tetrahedron 1994, 4399)

    Knochel et al. (Chem. Eur. J. 1998, 4, 950-968), Hayashi et al. (J. Chem. Soc., Chem. Commun. 1989, 495-496) und Ikeda et al. (Tetrahedron Lett. 1996, 4545-4448) beschreiben Pd-Komplexe mit C 2-symmetrische Ferrocenyl-(bis-tertiärphosphin)-Liganden. Allerdings wurden diese Komplexe lediglich bei asymmetrischen Allylierungen eingesetzt. Deren Verwendung als Katalysatoren bei der enantioselektiven Hydrierung ist bislang nicht bekannt.Knochel et al. (Chem. Eur. J. 1998, 4, 950-968), Hayashi et al. (J. Chem. Soc., Chem. Commun. 1989, 495-496) and Ikeda et al. (Tetrahedron Lett. 1996, 4545-4448) describe Pd complexes with C 2 -symmetric ferrocenyl (bis-tertiary phosphine) ligands. However, these complexes were used only in asymmetric allylation. Their use as catalysts in the enantioselective hydrogenation is not yet known.

    Yamamoto et al. (Bull. Chem. Soc. Jpn. 1980, 53, 1132-1137) berichteten über den Einsatz von nicht C 2-symmetrischen Ferrocenyl-(bis-tertiär-phosphin)-Liganden in der enantioselektiven homogenen katalytischen Hydrierung. Mit diesen Liganden erhält man jedoch nur sehr vereinzelt gute Enantiomerenüberschüsse.Yamamoto et al. (Bull. Chem. Soc., Jpn., 1980, 53, 1132-1137) reported the use of non- C 2 -symmetric ferrocenyl (bis-tertiary phosphine) ligands in enantioselective homogeneous catalytic hydrogenation. With these ligands, however, only very isolated enantiomeric excesses are obtained.

    Die DE 19827311.8 und Kang et al. (Tetrahedron Lett. 1998, 39, 5523-5526) offenbaren C 2-symmetrische Ferrocenylkomplexe als geeignete Katalysatoren für die enantioselektive Hydrierung von Acetamidozimtsäurederivate.DE 19827311.8 and Kang et al. (Tetrahedron Lett. 1998, 39, 5523-5526) disclose C 2 -symmetric ferrocenyl complexes as suitable catalysts for the enantioselective hydrogenation of acetamidocinnamic acid derivatives.

    Aufgabe der vorliegenden Erfindung ist die Angabe eines Verfahrens zur homogenen katalytischen enantioselektiven Hydrierung weiterer ungesättigter Systeme mit Hilfe C 2-symmetrischer Ferrocenylkatalysatoren.The object of the present invention is to specify a process for the homogeneous catalytic enantioselective hydrogenation of further unsaturated systems with the aid of C 2 -symmetric ferrocenyl catalysts.

    Unter Mehrfachbindungen werden im Rahmen der Erfindung Doppel-Bindungen zwischen einem Kohlenstoffatom und einem weiteren Kohlenstoffatom oder Sauerstoffatom oder Stickstoffatom verstanden.Under multiple bonds are within the scope of the invention Double bonds between a carbon atom and a another carbon atom or oxygen atom or Understood nitrogen atom.

    Gelöst wird diese Aufgabe durch ein Verfahren gemäß Anspruch 1. Bevorzugte Ausführungsformen sind Gegenstand der von Anspruch 1 abhängigen Unteransprüche.This problem is solved by a method according to Claim 1. Preferred embodiments are the subject The dependent of claim 1 dependent claims.

    Dadurch, daß man zur homogenen katalytischen enantioselektiven Hydrierung von Verbindungen der allgemeinen Formel (I)

    Figure 00040001
    By allowing the homogeneous catalytic enantioselective hydrogenation of compounds of general formula (I)
    Figure 00040001

    Katalysatoren der allgemeinen Formel (II)

    Figure 00050001
       worin

  • R1, R2 unabhängig voneinander bedeuten H, O(C1-C8)-Acyl, N(C1-C8)-Alkyl2, (C1-C8)-Alkyl
  • R3 bedeutet (C6-C18)-Aryl,
  • R4 bedeutet Phenyl,
  • R5 bedeutet H.
  • und M ein Metallatom oder -ion der Nebengruppe 7 oder 8, wie z. B. Co, Ni, Rh, Ru, Ir, Pd, Re oder Pt ist,
    • einsetzt, gelangt man in nichtvorhersehbarer Weise in guten bis sehr guten Ausbeuten und mit guten bis sehr guten Enantiomerenüberschüssen zu den gewünschten hydrierten Derivaten. Catalysts of the general formula (II)
    Figure 00050001
    wherein
  • R 1 , R 2 independently of one another are H, O (C 1 -C 8 ) -acyl, N (C 1 -C 8 ) -alkyl 2 , (C 1 -C 8 ) -alkyl
  • R 3 is (C 6 -C 18 ) -aryl,
  • R 4 is phenyl,
  • R 5 is H.
  • and M is a metal atom or -ion of subgroup 7 or 8, such as. Co, Ni, Rh, Ru, Ir, Pd, Re or Pt,
    • used, one arrives in an unpredictable manner in good to very good yields and with good to very good enantiomeric excesses to the desired hydrogenated derivatives.

    Das erfindungsgemäße Verfahren kann vorteilhafter Weise bei einer Temperatur zwischen 0°C und 150°C, vorzugsweise zwischen 20°C und 80°C, durchgeführt werden.The inventive method can advantageously in a temperature between 0 ° C and 150 ° C, preferably between 20 ° C and 80 ° C, are performed.

    Der Wasserstoffdruck sollte während der Reaktion zwischen 10 kPa und 10000 kPa, vorzugsweise zwischen 50 kPa und 8000 kPa, liegen.The hydrogen pressure should be between during the reaction 10 kPa and 10000 kPa, preferably between 50 kPa and 8000 kPa, lie.

    Als Lösungsmittel können alle dem Fachmann geläufigen Lösungsmittel eingesetzt werden, vorausgesetzt sie stören diese nicht im Hinblick auf Ausbeute und chirale Induktion. Bevorzugt sind Ether, wie THF, DME, MTBE, Alkohole, wie MeOH, EtOH, Propanol, Butanol, zu verwenden. All solvents known to the person skilled in the art may be used as solvents Solvents are used, provided they interfere these are not in terms of yield and chiral induction. Preference is given to ethers, such as THF, DME, MTBE, alcohols, such as MeOH, EtOH, propanol, butanol.

    Die Bereitstellung der C 2-symmetrischen Katalysatoren kann entsprechend der DE 19827311.8 erfolgen.The provision of the C 2 -symmetric catalysts can be carried out according to DE 19827311.8.

    Die Ferrocenylkatalysatoren zeigen bei der homogenen enantioselektiven katalytischen Hydrierung ausgezeichnete Werte, wie folgende Tabelle 1 belegt.

    Figure 00080001
    The ferrocenyl catalysts show excellent values in the homogeneous enantioselective catalytic hydrogenation, as shown in Table 1 below.
    Figure 00080001

    Die Katalysatorkonzentration ist mit 1% in den genannten Beispielen bereits sehr niedrig. Sie kann jedoch für technische Anwendung weiter erniedrigt werden. Dies beides ist für die Anwendung der erfindungsgemäßen Liganden im technischen Maßstab sehr von Vorteil, da die Kosten für die nach diesem Verfahren gewonnenen Produkte entsprechend niedriger ausfallen und damit ein höherer ökonomischer Nutzen als bei Verwendung von Ligandensystemen des Standes der Technik garantiert wird. The catalyst concentration is 1% in the mentioned Examples already very low. She can, however, for technical application. Both is for the application of the ligands of the invention in technical scale very beneficial, since the cost of the according to this method obtained products accordingly lower and thus a higher economic Benefits of using state-of-the-art ligand systems the technology is guaranteed.

    Nutzen als bei Verwendung von Ligandensystemen des Standes der Technik garantiert wird.Benefits of using state-of-the-art ligand systems the technology is guaranteed.

    Der Rest R5 in den Komplexen kann u. a. zur Anbindung der erfindungsgemäßen Komplexe an eine polymere Matrix wie z. B. ein lineares PMMA, Polystyrol oder PEG sowie ein nichtlineares Dendrimer benutzt werden. Die Anbindung des Restes R5 an den Cyclopentadienylring des erfindungsgemäßen Komplexes ist bzgl. der freien Positionen und bzgl. des Ringes variabel. Mithin genügt die Anbindung des Polymers an einen Ring. Als Reste können alle dem Fachmann für diesen Zweck in Frage kommenden Reste verwandt werden. Eine geeignete Übersicht zur molekularen Vergrößerung von Komplexkatalysatoren bietet (Tetrahedron Asymmetry 1998, 9, 691-696). Bevorzugt besteht der Rest R5 aus der Anordnung B-X-Z, wobei B ein Rest der Gruppe CR8 2, NR8, O, S, SiR8 2, X ein Spacer, wie z. B. 1,4'-Biphenyl, 1-, 2-Ethylen, 1-, 3-Propylen, PEG-(2-10) und Z eine funktionelle Gruppe, wie z. B. die O-, NH-, COO-, CONH, Ethenyl-, NHCONH-, OCONH- oder NHCOO-Funktion, welche an ein wie oben geschildertes Polymer gebunden ist. Alternativ können die Reste R5 der beiden Cyclopentadienylringe über eine α,ω,-(C2-C4)-Alkylenbrücke miteinander verbunden sein.The radical R 5 in the complexes may, inter alia, for attachment of the complexes of the invention to a polymeric matrix such. As a linear PMMA, polystyrene or PEG and a non-linear dendrimer can be used. The attachment of the radical R 5 to the cyclopentadienyl ring of the complex according to the invention is variable with respect to the free positions and with respect to the ring. Thus, the attachment of the polymer to a ring is sufficient. As radicals, it is possible to use all radicals which are suitable for this purpose. A suitable overview of the molecular enlargement of complex catalysts offers (Tetrahedron Asymmetry 1998, 9 , 691-696). Preferably, the radical R 5 consists of the arrangement BXZ, where B is a radical of the group CR 8 2 , NR 8 , O, S, SiR 8 2 , X is a spacer, such as. B. 1,4 '-biphenyl, 1-, 2-ethylene, 1-, 3-propylene, PEG- (2-10), and Z is a functional group such. As the O, NH, COO, CONH, ethenyl, NHCONH, OCONH or NHCOO function, which is bonded to a polymer as described above. Alternatively, the radicals R 5 of the two cyclopentadienyl rings can be linked to one another via an α, ω, - (C 2 -C 4 ) -alkylene bridge.

    Das sich mit den C 2-symmetrischen Ferrocenylkomplexe neben den Acetamidozimtsäurederivaten auch andere ungesättigte Verbindungen in zum Teil recht hohen ee-Werten hydrieren lassen, war im Stand der Technik bisher nicht bekannt. Um so überraschender aber nicht minder vorteilhaft ist es, daß auch Verbindungen des Typs (I) enantioselektiv umgesetzt werden können.The hydrogenation of other unsaturated compounds in sometimes quite high ee values with the C 2 -symmetric ferrocenyl complexes in addition to the acetamidocinnamic acid derivatives has not hitherto been known in the prior art. However, it is all the more surprising but no less advantageous that even compounds of type (I) can be reacted enantioselectively.

    Als linear oder verzweigte (C1-C18)-Alkyl sind anzusehen Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, Isobutyl, sec-Butyl, tert-Butyl, Pentyl, Hexyl, Heptyl oder Octyl bis zu einem 18 C-Atome aufweisenden Rest samt aller seiner Bindungsisomeren. Der Rest (C1-C18)-Alkoxy entspricht dem Rest (C1-C18)-Alkyl mit der Maßgabe, daß dieser über ein Sauerstoffatom an das Molekül gebunden ist. Als (C2-C18)-Alkoxyalkyl sind Reste gemeint, bei denen die Alkylkette durch mindestens eine Sauerstoffunktion unterbrochen ist, wobein nicht zwei Sauerstoffatome miteinander verbunden sein können. Die Anzahl der Kohlenstoffatome gibt die Gesamtzahl der im Rest enthaltenen Kohlenstoffatome an.As a linear or branched (C 1 -C 18 ) alkyl are methyl, ethyl, n- propyl, isopropyl, n- butyl, isobutyl, sec- butyl, tert- butyl, pentyl, hexyl, heptyl or octyl up to a 18 C atoms having all the rest of its binding isomers. The radical (C 1 -C 18 ) -alkoxy corresponds to the radical (C 1 -C 18 ) -alkyl, with the proviso that it is bonded to the molecule via an oxygen atom. By (C 2 -C 18 ) alkoxyalkyl is meant residues in which the alkyl chain is interrupted by at least one oxygen function, whereby not two oxygen atoms can be linked together. The number of carbon atoms indicates the total number of carbon atoms contained in the radical.

    Die eben beschriebenen Reste können einfach oder mehrfach mit Halogenen und/oder N-, O-, P-, S-atomhaltige Reste substituiert sein. Dies sind insbesondere Alkylreste der oben genannten Art, welche eines oder mehrere dieser Heteroatome in ihrer Kette aufweisen bzw. welche über eines dieser Heteroatome an das Molekül gebunden sind. Für die (C1-C8)-Alkylreste gilt das oben gesagte entsprechend für einen max. 8 C-Atome enthaltenden Alkylrest.The radicals just described may be monosubstituted or polysubstituted by halogens and / or N, O, P, S atom-containing radicals. These are in particular alkyl radicals of the abovementioned type which have one or more of these heteroatoms in their chain or which are bonded to the molecule via one of these heteroatoms. For the (C 1 -C 8 ) -alkyl radicals, the statements made above apply correspondingly to a max. 8 C atoms containing alkyl radical.

    Unter (C3-C8)-Cycloalkyl versteht man Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl bzw. Cycloheptylreste etc. Diese können mit einem oder mehreren Halogenen und/oder N-, O-, P-, S-atomhaltige Reste substituiert sein und/oder N-, O-, P-, S-atomhaltige Reste im Ring aufweisen, wie z. B. 1-, 2-, 3-, 4-Piperidyl, 1-, 2-, 3-Pyrrolidinyl, 2-, 3-Tetrahydrofuryl, 2-, 3-, 4-Morpholinyl.By (C 3 -C 8 ) -cycloalkyl is meant cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radicals, etc. These may be substituted by one or more halogens and / or N, O, P, S atom-containing radicals and / or N-, O-, P-, S-atom-containing radicals in the ring, such as. 1-, 2-, 3-, 4-piperidyl, 1-, 2-, 3-pyrrolidinyl, 2-, 3-tetrahydrofuryl, 2-, 3-, 4-morpholinyl.

    Ein (C3-C8)-Cycloalkyl-(C1-C8)-Alkylrest bezeichnet einen wie oben dargestellten Cycloalkylrest, welcher über einen wie oben angegebenen Alkylrest an das Molekül gebunden ist.A (C 3 -C 8 ) -cycloalkyl (C 1 -C 8 ) -alkyl radical denotes a cycloalkyl radical as described above which is bonded to the molecule via an alkyl radical as indicated above.

    (C1-C18)-Acyloxy bedeutet im Rahmen der Erfindung einen wie oben definierten Alkylrest mit max. 18 C-Atomen, welcher über eine COO-Funktion an das Molekül gebunden ist. Für (C1-C8)-Acyloxy gilt entsprechendes.(C 1 -C 18 ) -Acyloxy in the context of the invention means an alkyl radical as defined above with max. 18 C atoms, which is bound to the molecule via a COO function. For (C 1 -C 8 ) acyloxy the corresponding applies.

    (C1-C18)-Acyl bedeutet im Rahmen der Erfindung einen wie oben definierten Alkylrest mit max. 18 C-Atomen, welcher über eine CO-Funktion an das Molekül gebunden ist. Für (C1-C8)-Acyl gilt entsprechendes. (C 1 -C 18 ) acyl in the context of the invention means an alkyl radical as defined above with max. 18 C atoms, which is bound to the molecule via a CO function. For (C 1 -C 8 ) acyl, the corresponding applies.

    (C1-C8)-Alkyloxycarbonylrest bedeutet im Rahmen der Erfindung einen wie oben definierten Alkylrest mit max. 8 C-Atomen, welcher über eine OCO-Funktion an das Molekül gebunden ist.In the context of the invention (C 1 -C 8 ) -alkyloxycarbonyl radical means an alkyl radical as defined above with max. 8 C atoms, which is bound to the molecule via an OCO function.

    Unter einem (C6-C18)-Arylrest wird ein aromatischer Rest mit 6 bis 18 C-Atomen verstanden. Insbesondere zählen hierzu Verbindungen wie Phenyl-, Naphthyl-, Anthryl-, Phenanthryl-, Biphenylreste, welche ggf. mit (C1-C8)-Alkoxy, NR6R7, (C1-C8)-Acyl, (C1-C8)-Acyloxy substituiert sein können.By a (C 6 -C 18 ) -aryl radical is meant an aromatic radical having 6 to 18 C atoms. These include, in particular, compounds such as phenyl, naphthyl, anthryl, phenanthryl and biphenyl radicals, which are optionally substituted by (C 1 -C 8 ) -alkoxy, NR 6 R 7 , (C 1 -C 8 ) -acyl, (C 1 -C 8 ) acyloxy may be substituted.

    Ein (C7-C19)-Aralkylrest ist ein über einen (C1-C8)-Alkylrest an das Molekül gebundener (C6-C18)-Arylrest.A (C 7 -C 19 ) -aralkyl radical is a (C 6 -C 18 ) -aryl radical bonded to the molecule via a (C 1 -C 8 ) -alkyl radical.

    Ein (C3-C18)-Heteroarylrest bezeichnet im Rahmen der Erfindung ein fünf-, sechs- oder siebengliedriges aromatisches Ringsystem aus 3 bis 18 C-Atomen, welches Heteroatome wie z. B. Stickstoff, Sauerstoff oder Schwefel im Ring aufweist. Als solche Heteroaromaten werden insbesondere Rest angesehen, wie 1-, 2-, 3-Furyl, wie 1-, 2-, 3-Pyrrolyl, 1-,2-,3-Thienyl, 2-, 3-, 4-Pyridyl, 2-, 3-, 4-, 5-, 6-, 7-Indolyl, 3-, 4-, 5-Pyrazolyl, 2-,4-, 5-Imidazolyl, Acridinyl, Chinolinyl, Phenanthridinyl, 2-, 4-, 5-, 6-Pyrimidinyl.In the context of the invention, a (C 3 -C 18 ) -heteroaryl radical denotes a five-, six- or seven-membered aromatic ring system comprising 3 to 18 C atoms, which heteroatoms such. B. nitrogen, oxygen or sulfur in the ring. Particular examples of such heteroaromatics are radicals such as 1-, 2-, 3-furyl, such as 1-, 2-, 3-pyrrolyl, 1-, 2-, 3-thienyl, 2-, 3-, 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7-indolyl, 3-, 4-, 5-pyrazolyl, 2-, 4-, 5-imidazolyl, acridinyl, quinolinyl, phenanthridinyl, 2-, 4- , 5-, 6-pyrimidinyl.

    Unter einem (C4-C19)-Heteroaralkyl wird ein dem (C7-C19)-Aralkylrest entsprechendes heteroaromatisches System verstanden.By (C 4 -C 19 ) heteroaralkyl is meant a heteroaromatic system corresponding to the (C 7 -C 19 ) aralkyl radical.

    Unter Carboxyschutzgruppe wird eine wie in J. Jones, The Chemical Synthesis of Peptides, Oxford Science Pub. 1991, S. 33ff dargestellte Gruppe verstanden.Under carboxy-protecting group is a compound as described in J. Jones, The Chemical Synthesis of Peptides, Oxford Science Pub. 1991 P. 33ff.

    Als Halogene kommen Fluor, Chlor, Brom und Iod in Frage.Suitable halogens are fluorine, chlorine, bromine and iodine.

    Unter Salzen versteht man ionische Additionsverbindungen aus starken Säuren wie HCl, HBr, H2SO4, H3PO4, CF3COOH, p-Toluolsulfonsäure, Methansulfonsäure und dem betrachteten Molekül.By salts is meant ionic addition compounds of strong acids such as HCl, HBr, H 2 SO 4 , H 3 PO 4 , CF 3 COOH, p-toluenesulfonic acid, methanesulfonic acid and the molecule under consideration.

    PEG bedeutet Polyethylenglykol.PEG means polyethylene glycol.

    Unter dem Begriff enantiomerenangereichert wird im Rahmen der Erfindung der Anteil eines Enantiomers im Gemisch mit seiner optischen Antipode in einem Bereich von >50 % und <100 % verstanden.The term enantiomerically enriched is used in the context the invention, the proportion of an enantiomer in admixture with its optical antipode in a range of> 50% and <100% understood.

    Unter dem Begriff diastereomerenangereichert versteht man den Überschuß eines Diastereomers gegenüber einem oder mehreren anderen.The term diastereomerically enriched means the excess of a diastereomer over one or several others.

    Die Nennung der erfindungsgemäßen Komplexe und Liganden beinhaltet im Rahmen der Erfindung alle möglichen Diastereomere, wobei auch die beiden optischen Antipoden eines jeweiligen Diastereomeren benannt sein sollen.The mention of the complexes and ligands according to the invention includes all possible within the scope of the invention Diastereomers, where also the two optical antipodes should be named a respective diastereomer.

    Unter Polymere werden im Rahmen der Erfindung eine polymere Matrix, wie z. B. lineares PMMA, Polystyrol oder PEG sowie nichtlineare Dendrimere, verstanden. Among polymers in the context of the invention, a polymeric Matrix, such as As linear PMMA, polystyrene or PEG and nonlinear dendrimers, understood.

    Die folgenden Beispiele sollen die Erfindung erläutern.The following examples are intended to illustrate the invention.

    Beispiele:Examples: Hydrierung von KetoesternHydrogenation of ketoesters

    In einem 25 ml Schlenkgefäß werden 0,01 mmol Ru(COD)2X und 0,01 mmol des Ferrocenylliganden in 1 ml Aceton unter Argon gelöst. Dann werden 0,022 mmol HBr (c = 0,3 M; hergestellt aus 48%iger HBr in einer geeigneten Menge MeOH) zur Lösung hinzugegeben und 30 min bei RT gerührt. Anschließend destilliert man das Aceton ab und löst den Rückstand in 12 ml des entsprechenden Lösungsmittels. Nach Zugabe von 1 mmol des Ketoesters wird die Lösung unter Argon in einen 100 ml Stahlautoklaven überführt und nach mehrmaligem Spülen mit H2 für 10 min bei dem entsprechenden Wasserstoffdruck auf Reaktionstemperatur erwärmt. Anschließend läßt man die Mischung 24 h rühren, filtriert und ermittelte den Enantiomerenüberschuß per HPLC.0.01 mmol Ru (COD) 2 X and 0.01 mmol of the ferrocenyl ligand are dissolved in 1 ml acetone under argon in a 25 ml Schlenk flask. Then, 0.022 mmol HBr (c = 0.3 M, prepared from 48% HBr in a suitable amount of MeOH) is added to the solution and stirred at RT for 30 min. The acetone is then distilled off and the residue is dissolved in 12 ml of the appropriate solvent. After addition of 1 mmol of the ketoester, the solution is transferred under argon into a 100 ml steel autoclave and heated after repeated rinsing with H 2 for 10 min at the appropriate hydrogen pressure to reaction temperature. The mixture is then allowed to stir for 24 h, filtered and the enantiomeric excess determined by HPLC.

    Trimethylbrenztraubensäureethylester:trimethylpyruvate:

  • Lösungsmittel: EtOHSolvent: EtOH
  • Reaktionstemp.: 50°CReaction temp .: 50 ° C
  • Druck: 3000 kPaPressure: 3000 kPa

    • Der Umsatz wurde mittels 1H-NMR bestimmt. Der Enantiomerüberschuss wurde mittels HPLC bestimmt (Chiralcel OD, n-Heptan / Isopropanol 99 :1; flow 0.6 mL / min, T = 20 °C: tR = 10.55 (S), 12.25 (R).The conversion was determined by means of 1 H-NMR. The enantiomeric excess was determined by HPLC (Chiralcel OD, n-heptane / isopropanol 99: 1, flow 0.6 mL / min, T = 20 ° C: t R = 10.55 ( S ), 12.25 ( R ).

    Benzylbrenztraubensäureethylester:Benzylbrenztraubensäureethylester:

  • Lösungsmittel: EtOHSolvent: EtOH
  • Reaktionstemp.: 50°CReaction temp .: 50 ° C
  • Druck: 3000 kPaPressure: 3000 kPa

    • Der Umsatz wurde mittels 1H-NMR bestimmt. Der Enantiomerüberschuss wurde mittels HPLC bestimmt (Chiralcel OD, n-Heptan / Isopropanol 95 :5; flow 0.6 mL / min, T = 20 °C: tR = 14.73 (S), 23.44 (R).The conversion was determined by means of 1 H-NMR. The enantiomeric excess was determined by HPLC (Chiralcel OD, n-heptane / isopropanol 95: 5, flow 0.6 mL / min, T = 20 ° C: t R = 14.73 ( S ), 23.44 ( R ).

    Hydrierung von ungesättigten Estern/Säuren Hydrogenation of unsaturated esters / acids

    In einem 25 ml Schlenkgefäß werden 0,01 mmol Ru(COD)2X und 0,01 mmol des Ferrocenylliganden in 12 ml des entsprechenden Lösungsmittels gelöst. Nach Zugabe von 1 mmol des ungesättigten Esters wird die Lösung unter Argon in einen 100 ml Stahlautoklaven überführt und nach mehrmaligem Spülen mit H2 für 10 min bei dem entsprechenden Wasserstoffdruck auf Reaktionstemperatur erwärmt. Anschließend läßt man die Mischung 24 h rühren, filtriert, (verestert die ggf. eingesetzte Säure mit Me3SiCHN2) und ermittelte den Enantiomerenüberschuß per HPLC [(Chiralcel OJ, n-Heptan / Isopropanol 95 :5; flow 0.6 mL / min, T = 20 °C: tR = 18.05 (S), 21.13 (R)] bestimmt.In a 25 ml Schlenk tube, 0.01 mmol Ru (COD) 2 X and 0.01 mmol of the ferrocenyl ligand are dissolved in 12 ml of the appropriate solvent. After addition of 1 mmol of the unsaturated ester, the solution is transferred under argon in a 100 ml steel autoclave and heated after repeated rinsing with H 2 for 10 min at the appropriate hydrogen pressure to reaction temperature. The mixture is then allowed to stir for 24 h, filtered, the acid used is esterified with Me 3 SiCHN 2 and the enantiomeric excess is determined by HPLC [(Chiralcel OJ, n-heptane / isopropanol 95: 5; flow 0.6 mL / min). T = 20 ° C: t R = 18.05 ( S ), 21.13 ( R )].

    α-Phenylacrylsäure:α-phenylacrylic:

  • Lösungsmittel: THFSolvent: THF
  • Reaktionstemp.: 60°CReaction temp .: 60 ° C
  • Druck: 5000 kPaPressure: 5000 kPa

    • α-Phenylacrylsäuremethylester:α-phenylacrylate:

  • Lösungsmittel: MeOHSolvent: MeOH
  • Reaktionstemp.: 60°CReaction temp .: 60 ° C
  • Druck 5000 kPaPressure 5000 kPa

    • Claims (4)

    1. Process for the homogeneous, catalytic, enantioselective hydrogenation of compounds of the general formula (I)
      Figure 00210001
      wherein
      n is 0, 1,
      R = H, (C1-C18)-alkyl, (C6-C18)-aryl, (C7-C19)-aralkyl, (C1-C8)-alkyl- (C6-C18)-aryl, (C3-C8)-cycloalkyl, (C1-C8)-alkyl- (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl- (C1-C8)-alkyl or a carboxy protective group,
      R' = H, (C1-C18)-alkyl, (C6-C18)-aryl, (C7-C19)-aralkyl, (C3-C18)-heteroaryl, (C4-C19)-heteroaralkyl, (C1-C8)-alkyl- (C6-C18)-aryl, (C1-C8)-alkyl- (C3-C19)-heteroaryl, (C3-C8)-cycloalkyl, (C1-C8)-alkyl- (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkyl, said residues being optionally substituted with (C1-C8)-acyl or (C1-C8)-alkoxycarbonyl, wherein (C3-C18)-heteroaryl residue denotes a five-, six- or seven-membered aromatic ring system of 3 to 18 C atoms containing heteroatoms selected from nitrogen, oxygen or sulfur in the ring,
      X = O, CHR", NR",
      R" can be H, OH, R', (C1-C18)-alkoxy, (C2-C18)-alkoxyalkyl, (C1-C18)-acyl, (C1-C18)-acyloxy, with R" being able to take a different form for different positions,
      or R and R' or R' and R" or R" and R are connected together via a (C1-C4) bridge, which can be mono- or polysubstituted with linear or branched (C1-C8)-alkyl, (C1-C8)-acyl, (C1-C8)-alkoxy, (C2-C8)-alkoxyalkyl residues and/or can contain heteroatoms in the ring, selected from N, O, P, S,
      or
      wherein
      n is 1,
      R = H, (C1-C18)-alkyl, (C6-C18)-aryl, (C7-C19)-aralkyl, (C1-C8)-alkyl-(C6-C18)-aryl, (C3-C8)-cycloalkyl, (C1-C8)-alkyl- (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl- (C1-C8)-alkyl or a carboxy protective group,
      R' = H, (C1-C18)-alkyl, (C6-C18)-aryl, (C7-C19)-aralkyl, (C3-C18)-heteroaryl, (C4-C19)-heteroaralkyl, (C1-C8)-alkyl- (C6-C18)-aryl, (C1-C8)-alkyl-(C3-C19)-heteroaryl, (C3-C8)-cycloalkyl, (C1-C8)-alkyl-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C8)-alkyl, said residues being optionally substituted with (C1-C8)-acyl or (C1-C8)-alkoxycarbonyl, wherein (C3-C18)-heteroaryl residue denotes a five-, six- or seven-membered aromatic ring system of 3 to 18 C atoms containing heteroatoms selected from nitrogen, oxygen or sulfur in the ring,
      X = NR",
      R" can be H, OH, R', (C1-C18)-alkoxy, (C2-C18)-alkoxyalkyl, (C1-C18)-acyl, (C1-C18)-acyloxy, with R" being able to take a different form for different positions,
      or R and R' or R' and R" or R" and R are connected together via a (C1-C4) bridge, which can be mono- or polysubstituted with linear or branched (C1-C8)-alkyl, (C1-C8)-acyl, (C1-C8)-alkoxy, (C2-C8)-alkoxyalkyl residues and/or can contain heteroatoms in the ring, selected from N, O, P, S,
      with the aid of catalysts of the general formula (II)
      Figure 00230001
      wherein
      R1, R2, independently of one another, denote H, O(C1-C8)-acyl, N(C1-C8)-alkyl2, (C1-C8)-alkyl,
      R3 denotes (C6-C18)-aryl,
      R4 denotes phenyl,
      R5 denotes H,
      and M is a metal atom or ion from subgroup 7 or 8, such as e.g. Co, Ni, Rh, Ru, Ir, Pd, Re or Pt.
    2. Process according to claim 1, characterised in that the temperature during the reaction is between 0°C and 150°C, preferably between 20°C and 80°C.
    3. Process according to one or more of the above claims, characterised in that the hydrogen pressure during the reaction is between 10 kPa and 10000 kPa, preferably between 50 kPa and 8000 kPa.
    4. Process according to one or more of the above claims, characterised in that ethers, such as THF, DME, MTBE, or alcohols, such as MeOH, EtOH, propanol or butanol, are used as solvents during the reaction.
    EP99111460A 1998-06-19 1999-06-12 Process for enantioselective hydrogenation Expired - Lifetime EP0965574B1 (en)

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